1. Field of the Invention
The present invention relates to a method to determine the dose requirements of suramin used as a chemosensitizer to enhance the efficacy of other chemotherapeutic agents.
2. Description of the Prior Art
Suramin is an anticancer agent with modest activity in single agent therapy. A large number of previous studies have evaluated suramin in high-dose regimens, either as single agent or in combination with other chemotherapeutics. These studies, which aimed to achieve plasma concentrations between 150 and 300 μg/ml or about 100 to 200 μM, showed a modest activity of high-dose suramin for single agent therapy, in the face of extensive drug toxicity. (Eisenberger, et al (1995) J Clin Oncol 13:2174-2186). A typical suramin dosing schedule aimed at maintaining suramin plasma concentrations between 100 and 200 μg/ml consists of an initial administration of 2100 mg/m2 in the first week with the subsequent doses repeated every 28 days for 6 months or longer; the subsequent doses are adjusted using the Bayesian pharmacokinetic method (Dawson, et al (1998) Clin Cancer Res 4:37-44, Falcone, et al (1999) Cancer 86:470-476). Moreover, the methods of the art for using suramin in combination with other cytotoxic agents often administer high doses of suramin at a more frequent schedule or a longer duration compared to the frequency and the treatment duration for the other cytotoxic agents. For example, in the combination of suramin and doxorubicin for the treatment of androgen-independent prostate cancer, the duration of doxorubicin treatment was up to 20 weeks, whereas the duration of the suramin treatment was up to 45 weeks (Tu, et al (1998) Clin Cancer Res 4:1193-1201). For example, in the combination of suramin and mitomycin C for the treatment of hormone-resistant prostate cancer, suramin was given weekly whereas mitomycin C was given only every 5 weeks (Rapoport, et al (1993) Ann Oncol 4:567-573). At these doses and chronic treatments, suramin causes the following toxicity in a human patient: adrenal insufficiency, coagulopathy, peripheral neuropathy, and proximal muscle weakness (Dorr and Von Hoff, Cancer Chemotherapy Handbook, 1994, pp 859-866). To overcome the adrenolytic toxicity, patients on high-dose suramin regimens were co-administered replacement steroid treatments (Dorr and Von Hoff, id).
Combination regimens of suramin, at doses that result in relatively constant plasma concentrations of between about 100 to about 200 μM over several months, and other chemotherapeutic agents have shown either limited benefit or have resulted in toxicity that does not encourage further evaluation of these regimens (e.g., Miglietta, et al., J. Cancer Res. Clini. Oncol. 23:407-410, 1997; Falcone A, et al. Tumori 84:666, 1998; Falcone A, et al. Cancer 86:470, 1999; Rapoport B, et al. Ann Oncol 4:567, 1993).
The lack of synergistic interaction between suramin, at plasma concentrations between about 100 to about 200 μM maintained for several months, and other chemotherapeutic agents may be a result of the cell cycle perturbation caused by suramin; suramin at constant concentrations of above 50 μM maintained for at least one or two days has been shown to induce cell cycle arrest with accumulation of cells at different phases of the cell cycle and may therefore interfere with the activity of other chemotherapeutic agents that act on other phases of the cell cycle, as well as interfere with the activity of other chemotherapeutic agents whose activity depends on the ability of cells to progress through the cell cycle (Qiao L, et al. Biochem Biophys Res Commun 201:581, 1994; Howard S, et al. Clin Cancer Res 2:269, 1996; Palayoor S T, et al., Radiat Res, 148:105-114, 1997).
Applicants have disclosed in a previous patent application (PCT/US00/40103) that acidic and basic fibroblast growth factors (aFGF and bFGF) present in tumor tissues induce resistance of tumor cells to chemotherapy, and that this FGF-mediated resistance can be overcome by low concentrations of suramin of less than about 50 μM. However, it is not known whether the chemosensitizing effect of suramin would be diminished at higher doses delivering higher plasma concentrations in vivo.
The present invention shows that only low doses of suramin, which yielded between about 10 to about 50 μM plasma concentrations over the duration (e.g., 6 hours) when a chemotherapeutic agent (e.g., paclitaxel) was present in the plasma at therapeutically significant levels, enhanced the efficacy of chemotherapy in tumor-bearing animals. In contrast, high doses of suramin, that yielded concentrations between about 300 to about 650 μM over about the same duration, did not enhance the efficacy and only enhanced the toxicity of chemotherapy. Similarly, Applicants disclose the results of a Phase I trial, showing that addition of low dose suramin, that yielded between about 10 to about 50 μM plasma concentrations, over the duration when other chemotherapeutic agents (i.e., paclitaxel and carboplatin) were present at therapeutically significant levels, enhanced the response of cancer patients to a standard therapy of paclitaxel plus carboplatin. These findings are surprising in view of the prior art teaching that suramin does not improve the efficacy of other chemotherapeutic agents in human patients (Miglietta, et al, Falcone A, et al., 1998; Falcone A, et al., 1999; Rapoport, et al., 1993). These findings also are highly counter-intuitive, as it is generally believed that administration of a higher drug dose yields a greater effect rather than a lower effect, as compared to a lower dose. Furthermore, the low-dose suramin treatment did not induce adrenal insufficiency and, accordingly, replacement steroid therapy was not necessary in patients receiving low-dose suramin.
Previous studies to guide the dose selection of patients treated with high-dose suramin have used a Bayesian pharmacokinetic method, entailing continuous suramin pharmacokinetic monitoring that requires measurement of actual plasma concentrations in each patient over several months. This earlier approach is a highly labor-intensive and costly procedure that can only be performed in a limited number of clinical centers (Reyno L M, et al. J Clin Oncol 13:2187-2195, 1995), and, therefore, has limited applicability.
The application of population pharmacokinetics permitted the development of more easily applied fixed dosing schedules (Reyno L M, et al. J Clin Oncol 13:2187-2195, 1995; Small E, et al. J Clin Oncol 18:1440-1450, 2000). These schedules used the same initial dose on a per body surface area basis for all patients. Subsequent doses were reduced according to predetermined schedules. These regimens were designed to maintain constant and high plasma concentrations in the range of 100 to 200 μM, over long treatment durations of more than two months. In addition, these studies were limited to male patients with prostate cancer. Consequently, these regimens could not be applied to the use of suramin in combination therapy as a chemosensitizer in both male and female patients. As a chemosensitizer, the plasma concentrations of suramin are maintained at a narrow range of much lower levels (e.g., between about 10 to about 50 μM, e.g., below 300 to 650 μM), and only transiently while other chemotherapeutic agents are present at therapeutically significant concentrations (e.g., less than one week).
The fixed dosing schedules described in the prior art (Reyno, et al, Small E, et al) also do not offer provisions for deviation from the planned treatment schedule. However, in clinical practice, treatment delay due to toxicity or scheduling conflicts is very common. This, in turn, makes the fixed dosing schedules an impractical approach for administering suramin.
Further, the invention discloses a 180% inter-subject variability in suramin disposition in cancer patients, in part due to slower drug elimination in female patients compared to male patients. This gender-related difference in suramin elimination has not been previously demonstrated. The large inter-subject variability indicates that administering the same dose of suramin will not result in the same, desired plasma concentrations in all patients.
Accordingly, the methods described in the prior art for calculating the dose of suramin used as a cytotoxic agent cannot be used for calculating the suramin dose used as a chemosensitizer.
The invention discloses a simple and practical method to calculate a suramin dose in individual patients, based on the target chemosensitizing suramin concentrations and duration of suramin exposure (e.g., plasma concentrations of between about 10 to about 50 μM maintained over 48 hours), and demographic characteristics of a patient including, but not limited to, the squared value of the body surface area and gender of a patient, and the duration between treatments. This new method, therefore, can be used to calculate the suramin dose for use as a chemosensitizer, in both male and female patients, and can accommodate delay in treatments.
For other drugs where the maintenance of a narrow range of exposure is required, various other methods have been devised. For example, for the administration of carboplatin, a narrow range of integrated product of concentration and time (area under the concentration-time curve) is desired, and the carboplatin dose is calculated based on a patient's creatinine clearance (Calvert, et al, J. Clin. Onc. 7:1748, 1989). There is no disclosure, however, of a method to calculate the dose requirements for low-dose suramin that produces chemosensitization.